Pain is an essential protective mechanism that the body uses to alert or prevent further damage. Pain sensation is a complex event involving perception, transmission, processing, and response. Neurons at different levels (peripheral, spinal cord, and brain) are responsible for these pro- or antinociceptive activities to ensure an appropriate response to external stimuli. The terminals of these neurons, both in the peripheral endings and in the synapses, are equipped with G protein-coupled receptors (GPCRs), voltage- and ligand-gated ion channels that sense structurally diverse stimuli and inhibitors of neuronal activity. This review will focus on the largest class of sensory proteins, the GPCRs, as they are distributed throughout ascending and descending neurons and regulate activity at each step during pain transmission. GPCR activation also directly or indirectly controls the function of co-localized ion channels. The levels and types of some GPCRs are significantly altered in different pain models, especially chronic pain states, emphasizing that these molecules could be new targets for therapeutic intervention in chronic pain.